18 May 2012. Since soldiers stumbled out of World War I with panic attacks, nightmares, and other signs of shell shock, debate has raged over the nature of this trauma: Is it purely psychological, or are physical brain changes to blame? Research in the May 16 Science Translational Medicine convincingly supports the latter. Scientists at Boston University School of Medicine, Massachusetts, report that brains of blast-exposed military veterans pathologically resemble those of athletes who develop a tau-linked neurodegenerative disorder from repetitive head injuries. “Whether on a ball field in suburban Massachusetts or on the battlefield in Afghanistan, as far as the physics is concerned, it’s the same story,” said first author Lee Goldstein, who led the study with senior investigator Ann McKee of BU and the Veterans Affairs Boston Healthcare System and collaborators elsewhere. Rotational acceleration causes the head to swivel, and in normal mice subjected to a single blast, the “bobblehead effect” induces tau pathology, neurodegeneration, and learning and memory deficits resembling chronic traumatic encephalopathy (CTE). In this blast neurotrauma model, holding the head still during the blast reduced cognitive losses. Having a mouse model that recapitulates key aspects of CTE is a big step forward, experts say, as it enables experiments toward diagnosis and therapy development that were not previously possible.
Some 10 to 20 percent of U.S. military personnel deployed to Iraq and Afghanistan have suffered traumatic brain injuries (TBIs), many from exposure to explosive blasts (Wilk et al., 2010; see also U.S. Department of Defense numbers). People with blast-related injury present with symptoms similar to the ones reported by athletes who are later diagnosed with CTE, a tauopathy associated primarily with repeated concussions. Yet in a recent case study, scientists also found CTE pathology in the brain of a blast-exposed Iraqi war veteran (Omalu et al., 2011), suggesting that blast trauma and sports-related head injuries may share biomechanical underpinnings.
In the current paper, McKee and colleagues analyzed a case series of four postmortem brains from U.S. military veterans with blast exposure and/or concussive injury. They compared these with two other groups (four brains each): young athletes who suffered repeated head blows playing football or wrestling, and normal controls who died young with no blast exposure or concussive injury. In all, the group has analyzed some 60 cases of CTE due to different causes thus far.
The veteran and athlete brains showed pure tauopathy (i.e., no amyloid plaques), and were pathologically indistinguishable from each other. Both had pronounced neurofibrillary and glial tangles with phosphorylated tau, as well as distorted axons, activated microglia, and other CTE-like pathology—none of which appeared in the control brains. The findings were “readily differentiated from neuropathology associated with Alzheimer’s disease, frontotemporal dementia, and other age-related neurodegenerative disorders,” the authors wrote.
Still, the case series was small and cannot determine causality. “It’s like looking at the last frame of a movie and trying to figure out the plot line,” Goldstein said. “We’re looking at pathology years after the trauma has occurred.” Further complicating matters, many veterans also played contact sports, and could have whacked their heads in fights or car accidents. “You could do a hundred cases and not get around that,” Goldstein said.
This overlap prompted the researchers to develop a blast neurotrauma model. Lab mice do not play football or go to war, and have no prior head trauma. “They are a completely clean group,” Goldstein said. His team subjected 2.5-month-old mice to a single blast calculated to simulate what soldiers experience in the military setting, about 5.8 kilograms of TNT at 5.5 meters. Analyzed two weeks later, the mouse brains had no gross abnormalities or evidence of concussion. However, the researchers did find CTE-like tau pathology and neurodegeneration, as well as disrupted synaptic long-term potentiation and problems with learning and memory that lasted at least a month. “We were floored. We weren’t expecting this,” Goldstein said. “We were just using these mice to calibrate the gas tube in our blast study, thinking we would need multiple blasts and/or human tau transgenic mice to see tau pathology.”
In separate experiments measuring intracerebral pressure changes and head movements in mice during blast exposure, it appeared that blast-induced head acceleration, not the pressure wave itself, was the likely mechanism leading to brain injury and CTE. To test that idea, the researchers immobilized the animals’ heads during a single blast exposure, and found this could largely restore blast-induced cognitive deficits.
“This paper is a real tour de force. It’s an absolutely huge advance to the field,” said Elaine Peskind of the VA Puget Sound Health Care System and the University of Washington, Seattle. Using neuroimaging to study the brains of blast-exposed Iraq veterans, Peskind and colleagues have found they have lower glucose metabolism, poor structural integrity, and functional brain changes resembling those in early mild cognitive impairment (see ARF related news story). Her lab is also collecting cerebrospinal fluid data on these veterans.
Nigel Cairns of Washington University School of Medicine, St. Louis, Missouri, heard some of the new data presented at a recent symposium on military risk factors for AD. “The blast model is quite sound,” he told Alzforum. “From the pathology point of view, the lesions are comparable to those seen in human disease.” He noted minor differences—for example, tau aggregating less in blast-exposed mice than in people with CTE.
Scientists are working on other mouse models of TBI, too. In the May 9 Journal of Neuroscience, Kimberle Jacobs and colleagues at Virginia Commonwealth University, Richmond, use a yellow fluorescent protein (YFP)-expressing mouse to study electrophysiological consequences of TBI in neurons within living cortical slices. Other TBI animal models took the stage at a recent Keystone symposium on chronic encephalopathies (see ARF related conference story).
Meanwhile, new research published online May 16 in Neurology strengthens the idea that repeated head impacts can harm cognition. In a prospective cohort study, Thomas McAllister of Dartmouth Medical School in Lebanon, New Hampshire, and colleagues compared 214 college football and ice hockey players with 45 college athletes in non-contact sports. The results suggest that a single season of head impacts—measured by helmets with incorporated accelerometers—impairs learning in some athletes.
“These studies are coming together,” Cairns said. “If the head is exposed to trauma in a number of different settings, the sequelae are likely to be similar.” (See ARF Webinar.)
Genetics may also play a role, as suggested in a Science Translational Medicine editorial accompanying the paper on CTE in blast-exposed military veterans. There, Sam Gandy of Mount Sinai School of Medicine, New York, and Steven DeKosky of the University of Virginia School of Medicine, Charlottesville, highlight ApoE4 as a potential risk factor for CTE. However, among the CTE cases analyzed thus far at Boston University, ApoE genotype does not seem to influence CTE severity, Goldstein told ARF.
Does CTE pathology resulting from head trauma predispose people to Alzheimer’s disease? The blast neurotrauma mouse model could help address the question. The current study looked at relatively young (2.5-month-old) mice. If, however, the researchers found amyloid plaques a year later, “that would be a clear indication that head trauma accelerates development of AD,” Cairns said. Further clues could come through a joint project by the U.S. Department of Defense (DoD) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Under the initiative, 210 U.S. military veterans will be analyzed using ADNI protocols for brain amyloid imaging and Aβ and tau CSF biomarker analysis. Recruitment is slated to begin this fall, said lead investigator Michael Weiner of the University of California, San Francisco (see also Weiner comment on related editorial).
Ironically, while CTE pathology lacks a defining component of Alzheimer’s disease—amyloid plaques—the neuroanatomist who first described shell shock syndrome in World War I veterans was none other than that disease’s eponymous father, Alois Alzheimer, in his article Der Krieg und die Nerven: Breslau, Verlag von Preuf & Jünger, 1915 (see ARF related news story).
One future question this new research raises in some researchers’ minds is whether some cases of PTSD, for example, among veterans, might represent a prodromal form of CTE. PTSD is a clinical diagnosis, CTE primarily a pathological one, though that is beginning to change.—Esther Landhuis.
Goldstein LE, Fisher AM, Tagge CA, Zhang XL, Velisek L, Sullivan JA, Upreti C, Kracht JM, Ericsson M, Wojnarowicz MW, Goletiani CJ, Maglakelidze GM, Casey N, Moncaster JA, Minaeva O, Moir RD, Nowinski CJ, Stern RA, Cantu RC, Geiling J, Blusztajn JK, Wolozin BL, Ikezu T, Stein TD, Budson AE, Kowall NW, Chargin D, Sharon A, Saman S, Hall GF, Moss WC, Cleveland RO, Tanzi RE, Stanton PK, McKee AC. Chronic Traumatic Encephalopathy in Blast-Exposed Military Veterans and a Blast Neurotrauma Mouse Model. Sci Transl Med. 2012 May 16. Abstract
Gandy S and DeKosky ST. APOE e4 Status and Traumatic Brain Injury on the Gridiron or the Battlefield. Sci Transl Med. 2012 May 16. Abstract